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Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: relationship with suppression of circulating TGF-beta1.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2010 Sep; Vol. 88 (3), pp. 360-8. Date of Electronic Publication: 2010 Jul 21. - Publication Year :
- 2010
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Abstract
- Oltipraz is a potential candidate drug for the treatment of liver fibrosis (LF) and liver cirrhosis (LC). The pharmacokinetics of oltipraz and its major rearranged metabolite (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine (RM)) were evaluated after single-dose (30-90 mg) and multiple-dose (60 mg b.i.d. or 90 mg q.d. for 24 weeks) oral administration of oltipraz to patients with LF or LC. Oltipraz was safe and well tolerated in both studies. In the single-dose study, the area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)), and terminal half-life (t(1/2)) of oltipraz as well as the AUC of its RM were dose dependent. Oltipraz was rapidly absorbed; the time to reach C(max) (T(max)) was 2-4 h. The conversion of oltipraz to RM was also rapid and substantial (AUC of RM from time 0 to the last measured concentration (AUC(last, RM))/AUC(last, oltipraz), 42-61%). In the multiple-dose study, the level of transforming growth factor-beta1 (TGF-beta1) (a blood fibrosis marker) was suppressed at steady-state plasma concentrations of approximately 20-60 ng/ml of oltipraz or of approximately 60-140 ng/ml of oltipraz plus RM. Overall, the pharmacokinetics, safety, and efficacy of oltipraz suggest that it may be helpful in the treatment of patients with LF or LC, at an optimal dosing regimen.
- Subjects :
- Administration, Oral
Adult
Antiviral Agents administration & dosage
Antiviral Agents pharmacology
Area Under Curve
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Female
Half-Life
Humans
Liver Cirrhosis pathology
Male
Middle Aged
Pyrazines administration & dosage
Pyrazines pharmacology
Thiones
Thiophenes
Antiviral Agents pharmacokinetics
Liver Cirrhosis drug therapy
Pyrazines pharmacokinetics
Transforming Growth Factor beta1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 88
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 20664537
- Full Text :
- https://doi.org/10.1038/clpt.2010.89